Melanoma is a potentially fatal form of skin cancer that arises from isolated melanocytes or nevi (moles), after exposure to ultraviolet (UV) radiation. New therapies have not significantly improved survival for most patients with advanced melanoma, and although photoprotection has long been promoted by healthcare professionals, melanoma incidence continues to rise. Conventional chemoprevention strategies pose several problems when applied to melanoma, including: 1) administration of a drug of unknown chronic toxicity, 2) lack of biomarkers serving as surrogate indicators of efficacy for tumor development of long latency, and 3) lack of detailed information about genetic modifiers and biomarkers that facilitate assessment of patient risk for disease and capacity to respond to the agent. We propose a novel paradigm for melanoma chemoprevention using N- acetylcysteine (NAC), a potent antioxidant that is metabolized to cysteine (Cys) and converted to glutathione (GSH). We believe oxidative stress/damage in nevi is a viable surrogate for melanoma risk, and propose that reduced melanoma risk in humans can be inferred by protection of nevi from UV-induced oxidative changes. We hypothesize that administration of NAC around the time of UV exposure will reduce melanoma risk in high- risk patient populations with genetic susceptibility to UV-induced oxidative stress, and examination of key genetic variants will identify which individuals are most likely to benefit from chemoprotection. We propose a placebo-controlled trial in 100 patients designed to validate potential genetic and functional markers of susceptibility to UV-induced oxidative stress and protection by NAC. PUBLIC HEALTH RELEVANCE: Melanoma is a potentially fatal skin cancer, and there is lack of available effective therapies for patients with advanced disease. Oxidative stress plays a key role in UV-induced melanoma. The proposed studies will examine whether the antioxidant NAC can effectively protect patient's moles against UV-induced oxidative stress/damage, and investigate biomarkers to identify which patients are most likely (or unlikely) to benefit from thi novel strategy for melanoma chemoprevention. This project is particularly timely given the increasing incidence of melanoma.